Synthesis method of epothilone key intermediate

Abstract

The invention discloses a synthesis method of an epothilone key intermediate. The method comprises the following steps: carrying out addition reaction on a compound 1 and TMSCN in an ether solvent under the promotion of lithium chloride to generate a compound 2; carrying out substitution reaction on the compound 2 and a compound 3 under the action of alkali to generate a compound 4; the preparation method comprises the following steps: carrying out Ir-f-phamidol catalysis and TBDPSCl condensation on a compound 4, carrying out a reaction with tert-butyl hydroperoxide to generate a compound 7, carrying out a hydrogenation reaction and an oxidation reaction on the compound 7 to generate an epothilone key intermediate compound 9, and carrying out deprotection and reprotection on the compound 9 to generate another epothilone key intermediate compound 10; the compound 9 is used for synthesizing 3-deoxyepothilone B or D, and the compound 10 is used for synthesizing epothilone B or D. According to the method, the epothilone intermediate can be simply and efficiently synthesized, the reaction operation is simple, the amplification is easy, and a new method and way are provided for the synthesis of the epothilone intermediate.

Description

Technical Field

[0001] This application relates to the field of epomomycin intermediate synthesis technology, and in particular to a method for synthesizing a key epomomycin intermediate. Background Technology

[0002] The epochyrimycin family of natural products comprises a class of naturally occurring cytotoxic compounds with a 16-membered lactone ring as the central component. To date, six epochyrimycin derivatives have been reported, namely epochyrimycin AF. Epochyrimycin A and B were isolated from the South African soil myxobacterium Soce 90 by German natural product chemist Höfle et al. (Höfle, G.; Bedorf, N.; Steinmol, LH; Schomburg, D.; Gerth, K.; Reichenbach, H. Angew. Chem. Int. Ed. 1996, 35, 1567-1569). Subsequently, epochyrimycin CF was isolated. In 1995, Bollag et al. discovered that the mechanism of action of this class of compounds is very similar to that of paclitaxel, namely, by inhibiting the depolymerization of tubulin, forming stable cellular microtubules, making it difficult for the spindle to form, thereby inhibiting the mitosis of cancer cells, arresting the tumor cell cycle in the G2 / M phase, inhibiting cell growth, and inducing tumor cell apoptosis (Bollag, DM; McQuenney PA; Zhu J. et al. Cancer Res. 1995, 55, 23-25). The chemical structure of the natural product epomycin AF is as follows:

[0003]

[0004] The structural formula shows that epochyrimycin is a 16-membered macrocyclic lactone compound composed of one oxygen atom and 15 carbon atoms, with a side chain containing a thiazole ring attached to the 15-C position. The main differences between epochyrimycin AF and epochycin B lie in the C12- substituent and the oxidation states of C12 and C13. Among these natural epochyrimycin products, epochyrimycin B is currently the most widely studied compound.

[0005] Cancer remains one of the major diseases threatening public health. Epomycin possesses broad-spectrum antitumor activity, exhibiting excellent half-maximal inhibitory concentrations (IC50) at nanomolar levels against human tumors such as breast cancer, prostate cancer, lung cancer, and colon cancer, with antitumor activity 10 to 1000 times stronger than paclitaxel. Furthermore, it surpasses paclitaxel in antitumor activity, safety, water solubility, and synthetic efficiency, and is internationally recognized as a highly promising antitumor drug even more effective than paclitaxel. Moreover, epopycin is not affected by cellular detoxification proteins, thus avoiding the drug resistance issues associated with paclitaxel-like drugs. More importantly, due to the significantly simpler chemical structure of epopycin compared to paclitaxel, it offers greater potential for chemical modification and optimization. Therefore, the chemical synthesis of epopycin and its analogues is highly feasible and possesses significant scientific and applied value. Consequently, epopycin is considered the most promising "post-paclitaxel" drug currently on the market, with a very broad market prospect.

[0006] In the more than two decades since its discovery, edromycin research has made significant progress. Epomycin B lactam derivatives are currently the most effective compounds discovered. On October 16, 2007, the first edromycin lactam derivative (a semi-synthetic analog of edromycin B), ixabepilone (Bristol-Myers Squibb), received FDA approval for marketing in the United States, alone or in combination with capecitabine for the treatment of metastatic or advanced breast cancer. Ixabepilone is a next-generation microtubule inhibitor developed by Bristol-Myers Squibb. It can be used alone or in combination with other drugs to treat patients with advanced metastatic breast cancer resistant to anthracyclines and taxanes. Ixaspiron is the world's first epothilone-based antitumor drug, with antitumor activity 10-1000 times higher than that of the first-line anticancer drug paclitaxel (Cheng, Y.-H.; Chen, X.-H. World Clinical Drugs, 2011, 10, 619-623). The chemical structure of epothilone derivatives is as follows:

[0007]

[0008] Given the excellent antitumor activity and application value of epomomycin compounds, it is of great significance to develop efficient synthetic methods for epomomycin and its key intermediates. Summary of the Invention

[0009] The purpose of this application is to provide a novel method for synthesizing a key intermediate of epokine.

[0010] To achieve the above objectives, this application adopts the following technical solution:

[0011] This application discloses a method for synthesizing a key intermediate of epoetomycin, comprising: compound 1 and trimethylsilylcyanide (TMSCN) undergoing an addition reaction in an ether solvent under the promotion of lithium chloride to generate compound 2; compound 2 undergoing a substitution reaction with compound 3 under the action of a base to generate compound 4; compound 4 undergoing an asymmetric hydrogenation reaction under the catalysis of Ir-f-phamidol catalyst to generate compound 5; compound 5 and tert-butyldiphenylchlorosilane (TBDPSCl) undergoing a condensation reaction to generate compound 6; compound 6 reacting with peroxytert-butanol under the catalysis of SeO2 to generate compound 7; compound 7 undergoing a hydrogenation reaction under the catalysis of Ru[(S)DTBM-segephos]OAc2 to generate compound 8; compound 8 undergoing an oxidation reaction to generate compound 9; and compound 9 undergoing deprotection and reprotection to generate compound 10; wherein, compound 9 is a key intermediate for the synthesis of 3-deoxyepoetomycin B or 3-deoxyepoetomycin D, and compound 10 is a key intermediate for the synthesis of epoetomycin B or epoetomycin D;

[0012] Among them, compound 1 is shown as Formula 1, compound 3 is shown as Formula 2, compound 9 is shown as Formula 3, and compound 10 is shown as Formula 4.

[0013] Formula 1,

[0014] Formula 2,

[0015] Formula 3,

[0016] Formula 4 .

[0017] It should be noted that the synthetic method of this application can synthesize the key intermediates of epokine, namely compounds 9 and 10, in a simple and efficient manner. Moreover, the reaction operation is simple and easy to scale up, providing a new method and route for the synthesis of key intermediates of epokine.

[0018] In one implementation of this application, the synthesis method specifically includes the following steps:

[0019] .

[0020] In one implementation of this application, the solvent for generating compound 2 is tetrahydrofuran.

[0021] In one implementation of this application, the reaction temperature for generating compound 2 is -30℃ to 80℃.

[0022] In one implementation of this application, the base condition for generating compound 4 is a strong base.

[0023] In one implementation of this application, the strong base is lithium bis(trimethylsilylamino)amine (LiHMDS), lithium diisopropylamino (LDA), sodium hexamethylsilylamino (NaHMDS), or potassium hexamethyldisilamino (KHMDS).

[0024] In one implementation of this application, the solvent for generating compound 4 is at least one of tetrahydrofuran, methyl tert-butyl ether, and dioxane.

[0025] In one implementation of this application, the reaction temperature for generating compound 4 is -78°C to room temperature.

[0026] In one implementation of this application, the amount of Ir-f-phamidol catalyst is 0.001% to 1% of 4 moles of the compound.

[0027] In one implementation of this application, the reaction solvent for generating compound 5 is tetrahydrofuran, dichloromethane, trichloromethane, or toluene.

[0028] In one implementation of this application, the reaction temperature for generating compound 5 is room temperature.

[0029] In one implementation of this application, the reaction solvent for generating compound 6 is tetrahydrofuran, dichloromethane, or trichloromethane.

[0030] In one implementation of this application, the reaction temperature for generating compound 6 is room temperature.

[0031] In one implementation of this application, the reaction solvent for generating compound 7 is dichloromethane, n-hexane, chloroform, or N,N-dimethylformamide (DMF).

[0032] In one implementation of this application, the reaction temperature for generating compound 7 is room temperature.

[0033] In one implementation of this application, the reaction solvent for generating compound 8 is dichloromethane, n-hexane, chloroform, or N,N-dimethylformamide (DMF).

[0034] In one implementation of this application, the reaction temperature for generating compound 8 is room temperature.

[0035] In one implementation of this application, the oxidant used to generate compound 9 from compound 8 through an oxidation reaction is a pyridine sulfur trioxide complex.

[0036] In one implementation of this application, the reaction solvent for generating compound 9 is dichloromethane or trichloromethane.

[0037] In one implementation of this application, the reaction temperature for generating compound 9 is room temperature.

[0038] In one implementation of this application, the protecting group remover used to generate compound 10 is tetrabutylammonium fluoride (TBAF).

[0039] In one implementation of this application, the reaction solvent for generating compound 10 is dichloromethane or trichloromethane.

[0040] In one implementation of this application, the reaction temperature for generating compound 10 is room temperature to 50°C.

[0041] In one implementation of this application, the synthesis of epokilin B or epokilin D from compound 10 includes the following steps:

[0042] .

[0043] In one implementation of this application, the synthesis of 3-deoxyepomycin B or 3-deoxyepomycin D from compound 9 includes the following steps:

[0044] .

[0045] Due to the adoption of the above technical solutions, the beneficial effects of this application are as follows:

[0046] The method for synthesizing key intermediates of epomomycin presented in this application is simple and efficient for synthesizing key intermediates of epomomycin, compounds 9 and 10. The reaction operation is simple and easy to scale up, providing a new method and route for the synthesis of key intermediates of epomomycin. Attached Figure Description

[0047] Figure 1 It is compound 9 in the embodiments of this application. 1 H NMR spectrum;

[0048] Figure 2 It is compound 9 in the embodiments of this application. 13 C NMR spectrum;

[0049] Figure 3 It is compound 10 in the embodiments of this application. 1 H NMR spectrum;

[0050] Figure 4 It is compound 10 in the embodiments of this application. 13 C10 NMR spectrum. Detailed Implementation

[0051] The present application will now be described in further detail with reference to specific embodiments and accompanying drawings. In the following embodiments, many details are described to facilitate a better understanding of the present application. However, those skilled in the art will readily recognize that some features may be omitted in different situations, or may be replaced by other materials or methods. In some cases, certain operations related to the present application are not shown or described in the specification. This is to avoid obscuring the core parts of the present application with excessive description. For those skilled in the art, detailed description of these related operations is not necessary; the relevant operations can be fully understood based on the description in the specification and general technical knowledge in the art.

[0052] In this application, the serial numbers assigned to structural formulas or functional groups, such as "Compound 1" or "Formula 1," are used solely to distinguish the described objects and have no sequential or technical meaning. All reagents used in this application are commercially available or can be prepared using the methods described herein.

[0053] Example

[0054] The synthesis method of the key intermediate of epomycin in this example includes the following steps:

[0055]

[0056] Specifically, it includes:

[0057] Synthesis of Compound 2

[0058]

[0059] Trimethylsilyl cyanide (27.2 mL, 217 mmol, 1.5 eq.) and LiCl (0.5 M, 8.8 mL, 4.4 mmol, 0.03 eq.) were added at 0 °C to a dry THF (150 mL) solution of compound 1 (24.20 g, 145 mmol, 1.0 eq.). The mixture was stirred at room temperature for 1 h (Compound 1, CAS number 184246-38-6, can be synthesized in one step by the condensation reaction of 2-methyl-4-thiazolylcarbaldehyde (CAS: 20949-84-2) and propionaldehyde). The solution was diluted with Et2O (100 mL) and washed with saturated NaHCO3 solution (50 mL) and brine (50 mL). The layers were separated, and the aqueous phase was extracted with Et2O (50 mL × 2). The organic phase was collected, dried on anhydrous Na2SO4, and then the volatile components were removed under vacuum to obtain crude product 2, which was a pale yellow oil that could be used directly without further purification.

[0060] Data of 2: TLC: Rf = 0.5 (Petroleum ether / Ethyl acetate = 8 / 1); 1 H NMR(400 MHz, CDCl3) δ 7.05 (s, 1H), 6.67 (s, 1H), 4.90 (s, 1H), 2.71 (s, 3H),2.19 (d, J = 1.0 Hz, 3H), 0.23 (s, 9H); 3 C NMR (100 MHz, CDCl3) δ 165.2,151.7, 133.6, 122.0, 118.6, 117.9, 67.3, 19.4, 14.6, -0.2; RMS (ESI-TOF):Calcd for C 12 H 18 N2OSSi + [M+H] + : 267.0982, found 267.0983.

[0061]

[0062] In a 1000 mL flask, LiHMDS (1.0 M in THF, 174 mL, 174 mmol, 1.2 eq) was added to dry THF (360 mL). Compound 2 (dissolved in 40 mL THF) was slowly added to the flask and incubated at -78 °C for 10 min. After 30 min, compound 3 (CAS: 25996-10-5, synthesized from nerol via a one-step bromination reaction, nerol CAS: 106-25-2) (34.6 g, 160 mmol, 1.1 eq.) was dissolved in dry THF (100 mL) and then added dropwise to the solution. The mixture was stirred for another 20 min at the same temperature. The reaction was carefully quenched by adding saturated NH4Cl solution (100 mL) and extracted with Et2O (150 mL × 2). The combined organic layer was washed with water (80 mL) and brine (80 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The resulting residue was dissolved in THF (200 mL), and an aqueous solution of HCl (2N) was carefully added to pH = 2, followed by stirring overnight at room temperature. Subsequently, the mixture was diluted with Et₂O (150 mL) and washed with water (200 mL). The organic phase was separated, and an aqueous solution of NaOH (2 M) was added to pH = 11. After stirring for 5 min, the organic layer was separated, washed with water (100 mL) and brine (100 mL), dried over anhydrous Na₂SO₄, concentrated, and the residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 50 / 1–40 / 1) to give compound 4 (24.6 g), which was directly used for subsequent asymmetric hydrogenation.

[0063] Data of 4: TLC: Rf = 0.6 (Petroleum ether / Ethyl acetate = 8 / 1); 1 HNMR (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.33 (s, 1H), 5.41 (t, J = 6.4 Hz, 1H), 5.15 – 5.08 (m, 1H), 3.53 (d, J = 6.9 Hz, 2H), 2.75 (s, 3H), 2.22 (d, J = 0.9Hz, 3H), 2.10 – 2.05 (m, 4H), 1.75 (d, J = 1.1 Hz, 3H), 1.67 (s, 3H), 1.60(s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.8, 165.5, 152.0, 138.7, 137.3, 132.0,131.2, 124.1, 121.3, 117.6, 37.2, 32.4, 26.5, 25.8, 23.6, 19.4, 17.8, 13.7;HRMS (ESI-TOF): Calcd for C 18 H 25 NOS + [M+H] + : 304.1730, found 304.1731.

[0064] Synthesis of Compound 5

[0065]

[0066] The catalyst precursors [Ir(COD)Cl]₂ (134.4 mg, 0.2 mmol, 0.0025 eq.) and Rf-phamidol (239 mg, 0.42 mmol, 0.00525 eq.) were sequentially added to a 20 mL flask containing 10.0 mL of anhydrous THF under an argon atmosphere. The mixture was stirred at room temperature for 1 h, transferred to a 200 mL hydrogenation vessel, and then a THF solution (35 mL) of compound 4 and a solution of Cs₂CO₃ (2.60 g, 8.0 mmol, 0.1 eq.) were added. The vessel was placed in an autoclave, and then purged with 70 bar of H₂, and stirred at room temperature for 48 h. After slowly releasing the pressure, volatile components were removed under vacuum, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1-8 / 1) to give compound 5 (19.2 g, ee >99%), with an overall yield of 43% for the three steps.

[0067] Data of 5: TLC: Rf = 0.2 (Petroleum ether / Ethyl acetate = 8 / 1); 11H NMR (600 MHz, CDCl3) δ 6.93 (s, 1H), 6.55 (s, 1H), 5.17 (t, J = 7.0 Hz, 1H), 5.13 – 5.08 (m, 1H), 4.13 (t, J = 6.5 Hz, 1H), 2.70 (s, 3H), 2.37 – 2.31 (m, 2H), 2.09 – 2.05 (m, 2H), 2.03 (s, 3H), 1.72 (s, 3H), 1.68 (s, 3H), 1.60 (s, 3H);

[0068] 13 13C NMR (150 MHz, CDCl3) δ 164.6, 153.0, 142.0, 139.0, 132.0, 124.1, 120.6, 119.0, 115.5, 77.3, 34.2, 32.2, 26.6, 25.8, 23.7, 19.3, 17.8, 14.5; HRMS (ESI-TOF): Calcd for C 18 H 27 NOS + [M+H] + : 306.1886, found 306.1887; Optical Rotation: [α] D 28.4 = -4.3 (c 1.0, CH2Cl2). The enantiomeric excess (ee) of 21 was determined by HPLC on a chiral stationary phase. Chiral HPLC conditions: Chiralpak OD-H column, n-hexane / i-PrOH = 92 / 8, 1.0 mL / min, λ = 254 nm, tR (major) = 11.1 min.

[0069] Synthesis of Compound 6

[0070]

[0071] TBDPSCl (23 g, 84.6 mmol, 1.8 eq.) and imidazole (6.7 g, 98.7 mmol, 2.1 eq.) were added to anhydrous DCM (200 mL) in a solution of ethanol 5 (14.35 g, 47 mmol, 1.0 eq.). The mixture was stirred at room temperature for 3 h at 0 °C. The reaction was carefully quenched with saturated NaHCO3 solution (50 mL), and extracted with DCM (100 mL × 2). The combined organic layers were washed with water (80 mL) and brine (80 mL). The layers were separated, the organic phase was collected, dried over anhydrous Na2SO4, and volatile components were removed under vacuum. The purified organic phase was obtained by flash column chromatography (petroleum ether / ethyl acetate = 50 / 1) to give silyl ether 6 (24.24 g, 95%) as a colorless oily liquid.

[0072] Data of 6: TLC: Rf = 0.6 (Petroleum ether / Ethyl acetate = 8 / 1); 1 HNMR (600 MHz, CDCl3) δ 7.72 (d, J = 6.8 Hz, 2H), 7.66 (d, J = 6.8 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 7.40 – 7.35 (m, 3H), 7.31 (t, J = 7.4 Hz, 2H), 6.79(s, 1H), 6.26 (s, 1H), 5.05 (t, J = 6.8 Hz, 1H), 5.00 (t, J = 7.1 Hz, 1H), 4.19 (t, J = 6.6 Hz, 1H), 2.71 (s, 3H), 2.37 (dt, J = 14.1, 6.9 Hz, 1H), 2.31– 2.24 (m, 1H), 2.00 (s, 3H), 1.99 – 1.93 (m, 2H), 1.93 – 1.87 (m, 2H), 1.68(s, 3H), 1.61 (s, 3H), 1.58 (s, 3H), 1.10 (s, 9H); 13C NMR (150 MHz, CDCl3) δ164.2, 153.3, 141.5, 136.9, 136.2, 136.1, 134.6, 134.2, 131.4, 129.6, 129.5,127.53, 127.46, 124.5, 121.1, 119.8, 115.1, 79.7, 35.1, 32.1, 27.2, 26.6,25.8, 23.6, 19.5, 19.3, 17.7, 14.2; HRMS (ESI-TOF): Calcd for C 34 H 45 NOSSi + [M+H] + : 544.3064, found 544.3068; Optical Rotation: [α] D 28.8 = -17.7 (c 1.0,CH2Cl2).

[0073] Synthesis of Compound 7

[0074]

[0075] SeO2 (0.730 g, 6.58 mmol, 0.2 eq.) and tert-butyl peroxide (5.0–6.0 M in decane, 11.9 mL, 65.8 mmol, 2.0 eq.) were added sequentially to anhydrous DCM (65 mL). After cooling the solution to 0 °C, 22 (17.86 g, 32.9 mmol, 1.0 eq.) of anhydrous DCM (20 mL) was slowly added, and the mixture was stirred overnight. The reaction was carefully quenched with saturated Na2S2O3 solution (40 mL) and washed with 5% KOH aqueous solution (30 mL × 3). The layers were separated, the organic phase was collected, dried over anhydrous Na2SO4, volatile components were removed under vacuum, and the organic phase was dissolved in 80 mL of aqueous solution. NaBH4 (249 mg, 6.6 mmol, 0.2 eq.) was added in three portions at 0 °C. The reaction was stirred at this temperature for 0.5 h, and the mixture was carefully quenched with H2O. Most of the volatiles were removed under vacuum, the mixture was diluted with ethyl acetate (150 mL), and washed with brine. The organic phase was collected, dried over anhydrous Na2SO4, and the volatile components were removed under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1-16 / 1-4 / 1) to give pure oily product 7 (11 g, 60%), and the oily starting compound 6 (2.96 g) was recovered.

[0076] Data of 7: TLC: Rf = 0.2 (Petroleum ether / Ethyl acetate = 8 / 1); 1 HNMR (600 MHz, CDCl3) δ 7.69 (dd, J = 7.9, 1.2 Hz, 2H), 7.65 – 7.62 (m, 2H),7.43 – 7.39 (m, 1H), 7.35 (dd, J = 11.1, 4.3 Hz, 3H), 7.29 (t, J = 7.3 Hz,2H), 6.78 (s, 1H), 6.21 (s, 1H), 5.25 (td, J = 7.0, 1.1 Hz, 1H), 4.98 (t, J =7.1 Hz, 1H), 4.15 (t, J = 6.7 Hz, 1H), 3.94 (s, 2H), 2.69 (s, 3H), 2.34 –2.29 (m, 1H), 2.25 – 2.20 (m, 1H), 2.04 – 2.00 (m, 1H), 1.96 (d, J = 0.9 Hz,3H), 1.95 – 1.88 (m, 2H), 1.88 – 1.84 (m, 1H), 1.60 (s, 3H), 1.57 (s, 3H),1.07 (s, 9H); 13 C NMR (150 MHz, CDCl3) δ 164.5, 153.1, 141.4, 136.6, 136.2,136.1, 135.1, 134.6, 134.1, 129.63, 129.58, 127.6, 127.5, 125.7, 121.4,119.9, 115.1, 79.8, 68.9, 35.1, 31.5, 27.2, 25.9, 23.4, 19.5, 19.3, 14.1,13.7; HRMS (ESI-TOF): Calcd for C 34 H 45 NO2SSi + [M+H] + : 560.3013, found 560.3019;Optical Rotation: [α] D 28.8 = -20.6 (c 1.0, CH2Cl2).

[0077] Synthesis of Compound 8

[0078]

[0079] In an argon-filled glove box, a stir bar was added to a 200 mL hydrogenation vessel containing a solution of 16 (8.5 g, 15.2 mmol) in 30.4 mL of dry MeOH and 1.5 mL of H₂O, along with [Ru{(S)-DTBM-Segphos}(OAc)₂] (210 mg, 0.15 mmol, 0.01 eq). The vessel was placed in an autoclave and sealed. After being removed from the glove box, the autoclave was rinsed three times with H₂ and then pressurized to 100 bar of H₂. After stirring at room temperature for 14 h, the pressure was carefully released, and volatile components were removed under vacuum to obtain a crude residue oil. This crude oil was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 ~ 8 / 1) to give a colorless oily compound 8 (5.55 g, 65%).

[0080] Data of 8: TLC: Rf = 0.2 (Petroleum ether / Ethyl acetate = 8 / 1); 1 HNMR (400 MHz, CDCl3) δ 7.73 – 7.67 (m, 2H), 7.67 – 7.61 (m, 2H), 7.45 – 7.27(m, 6H), 6.78 (s, 1H), 6.22 (s, 1H), 5.00 (t, J = 7.1 Hz, 1H), 4.16 (t, J =6.5 Hz, 1H), 3.47 – 3.31 (m, 2H), 2.69 (s, 3H), 2.37 – 2.18 (m, 2H),, 2.11(brs, 1H), 1.95 (s, 3H), 1.89 – 1.75 (m, 2H), 1.56 (s, 3H), 1.54 – 1.49 (m,1H), 1.31 – 1.25 (m, 2H), 1.25 – 1.20 (m, 1H), 1.07 (s, 9H), 0.98 – 0.90 (m,1H), 0.86 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 164.5, 153.1, 141.6,137.1, 136.14, 136.10, 134.5, 134.1, 129.59, 129.55, 127.54, 127.48, 121.0,119.8, 115.0, 79.8, 68.1, 35.8, 35.2, 33.0, 32.0, 27.2, 25.2, 23.4, 19.5,19.2, 16.7, 14.2; HRMS (ESI-TOF): Calcd for C 34 H 47 NO2SSi + [M+H] + : 562.3170, found 562.3175; Optical Rotation: [α] D 28.9 = -22.0 (c 1.0, CH2Cl2).

[0081] Synthesis of Compound 9

[0082]

[0083] Triethylamine (9.1 mL, 65.3 mmol, 6.8 eq.) and pyridine sulfide (8.4 g, 52.8 mmol, 5.5 eq.) were added to solutions of compound 8 in DCM (35 mL) and DMSO (7.0 mL) (5.4 g, 9.6 mmol, 1.0 eq.), respectively, at 0 °C. The solutions were stirred at 0 °C for 30 min, the reaction was quenched with water (20 mL), and extracted with DCM (50 mL × 2). The bound organic layers were washed with saturated CuSO4 solution (100 mL × 2) and brine (100 mL). The layers were separated, and the bound organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. Purification by silica gel rapid column chromatography (petroleum ether / ethyl acetate = 40 / 1) yielded a colorless oily compound 9 (5.05 g, 94%).

[0084] Data of 15: TLC: Rf = 0.5 (Petroleum ether / Ethyl acetate = 8 / 1); 11H NMR (600 MHz, CDCl3) δ 9.55 (d, J = 1.9 Hz, 1H), 7.72 – 7.67 (m, 2H), 7.65 –7.61 (m, 2H), 7.43 – 7.39 (m, 1H), 7.35 (t, J = 7.1 Hz, 3H), 7.29 (t, J = 7.3Hz, 2H), 6.78 (s, 1H), 6.23 (s, 1H), 4.99 (t, J = 7.1 Hz, 1H), 4.15 (t, J =6.5 Hz, 1H), 2.70 (s, 3H), 2.30 (dt, J = 13.6, 6.8 Hz, 1H), 2.27 – 2.18 (m,2H), 1.97 (d, J = 0.7 Hz, 3H), 1.89 – 1.80 (m, 2H), 1.64 – 1.61 (m, 1H), 1.55(s, 3H), 1.30 – 1.25 (m, 2H), 1.23 – 1.17 (m, 1H), 1.07 (s, 9H), 1.03 (d, J =7.0 Hz, 3H); 13 13C NMR (150 MHz, CDCl3) δ 205.3, 164.3, 153.3, 141.4, 136.4,136.2, 136.1, 134.6, 134.1, 129.63, 129.58, 127.6, 127.5, 121.5, 119.8,115.2, 79.6, 46.4, 35.1, 31.8, 30.3, 27.2, 25.2, 23.4, 19.6, p19.4, 14.3,13.4; HRMS (ESI-TOF): Calcd for C 34 H 45 NO2SSi + [M+H] + : 560.3013, found 560.3019;Optical Rotation: [α] D 29.0 = -23.3 (c 1.0, CH2Cl2).

[0085] Synthesis of Compound 10

[0086]

[0087] Deoxy-TBAF (3.0 mL, 3.0 mmol, 1.0 M THF solution, 15 eq.) was added to a deoxy-THF (1.0 mL) solution of compound 9 (112 mg, 0.2 mmol, 1.0 eq.) at room temperature. The reaction was heated to 40 °C and stirred for 5 hours under an argon atmosphere. After completion, the flask was cooled to room temperature and quenched with saturated NH4Cl solution. The solution was diluted with EtOAc (10 mL), and the aqueous phase was extracted with EtOAc (5.0 mL × 2). The bound organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by rapid column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain a pale yellow residue, which was dissolved in 1.0 mL DCM. The flask was cooled to 0°C, and imidazole (41 mg, 0.6 mmol, 3.0 eq.) and TBSCl (66 mg, 0.44 mmol, 2.2 eq.) were added sequentially. The mixture was stirred at room temperature for 1 h, and the reaction was quenched with saturated NaHCO3 solution (1.0 mL). Extraction was performed using DCM (2.0 mL × 2). The combined organic layers were washed with distilled water (3.0 mL) and brine (3.0 mL). The layers were separated, the organic phase was collected, dried over anhydrous Na2SO4, and volatile components were removed under vacuum. The mixture was purified by flash column chromatography (petroleum ether / ethyl acetate = 40 / 1) to give a colorless, oily silyl ether compound 10 (71.4 mg, 82%).

[0088] Data of 10: TLC: Rf = 0.5 (Petroleum ether / Ethyl acetate = 8 / 1); 1 HNMR (400 MHz, CDCl3) δ 9.59 (d, J = 1.9 Hz, 1H), 6.91 (d, J = 4.3 Hz, 1H), 6.45 (s, 1H), 5.16 (t, J = 7.3 Hz, 1H), 4.12 – 4.03 (m, 1H), 2.70 (s, 3H),2.37 – 2.16 (m, 3H), 2.10 – 1.93 (m, 2H), 1.99 (s, 3H), 1.71 – 1.61 (m, 1H),1.66 (d, J = 0.9 Hz, 3H), 1.41 – 1.27 (m, 3H), 1.08 (d, J = 7.0 Hz, 3H), 0.88(s, 9H), 0.04 (s, 3H), -0.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 205.0, 164.3,153.1, 142.4, 136.0, 122.0, 118.6, 114.9, 78.8, 46.2, 35.3, 31.7, 30.2, 25.7,25.2, 23.3, 19.1, 18.1, 13.9, 13.2, -4.7, -5.1; HRMS (ESI-TOF): Calcd forC 24 H 42 NO2SSi + [M+H] + : 436.2700, found 436.2704; Optical Rotation: [α] D 26.3 = +1.7 (c 0.93, CH2Cl2).

[0089] Compound 9 can be synthesized to give 3-deoxyepomycin B and 3-deoxyepomycin D by the following steps:

[0090]

[0091] Specifically, it includes:

[0092] Compound 11

[0093]

[0094] Take a small vial dried in an oven, add TMSQn (0.60 g, 1.5 mmol, 0.15 eq.) and LiI (6.70 g, 50.0 mmol, 5.0 eq.), and under argon protection in DCM (25 mL) and Et2O (2.5 mL), stir at room temperature for 5 min, then cool to -78 °C. Dissolve compound aldehyde 9 in 2.0 mL of DCM (5.60 g, 10 mmol, 1.0 eq.) and add it to the solution. After rinsing with 0.5 mL of DCM, add DIPEA (5.2 mL, 30 mmol, 3.0 eq.) to the above system, and stir at this temperature for 15 min. Then heat the reaction system to -50 °C, and slowly add propionyl chloride (2.30 g in 10 mL DCM, 25 mmol, 2.5 eq.) using a syringe pump for 2.5 h. The mixture was stirred at this temperature for 3 h. The reaction was quenched with NaHCO3 solution (50 mL), diluted with Et2O (100 mL), and washed with water (50 mL). The layers were separated, and the aqueous layer was further extracted with Et2O (50 mL × 2). The combined organic matter was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1-20 / 1) to give an oily compound 11 (2.83 g, 46%), while compound 9 (1.57 g) was recovered.

[0095] Data of 11:

[0096] TLC: Rf = 0.35 (Petroleum ether / Ethyl acetate = 8 / 1); 1H NMR (600MHz, CDCl3) δ 7.73 – 7.67 (m, 2H), 7.66 – 7.61 (m, 2H), 7.40 (d, J = 7.4 Hz,1H), 7.38 – 7.33 (m, 3H), 7.29 (t, J = 7.3 Hz, 2H), 6.79 (s, 1H), 6.23 (s,1H), 4.98 (t, J = 7.1 Hz, 1H), 4.15 (t, J = 6.5 Hz, 1H), 4.08 (dd, J = 10.9,6.2 Hz, 1H), 3.73 – 3.67 (m, 1H), 2.69 (s, 3H), 2.30 (dt, J = 14.0, 6.8 Hz,1H), 2.26 – 2.17 (m, 1H), 1.97 (d, J = 0.8 Hz, 3H), 1.83 (t, J = 6.7 Hz, 2H),1.79 – 1.73 (m, 1H), 1.56 (s, 3H), 1.55 – 1.50 (m, 1H), 1.35 (d, J = 4.6 Hz,1H), 1.31 (d, J = 7.8 Hz, 3H), 1.25 – 1.18 (m, 2H), 1.06 (s, 9H), 0.81 (d, J= 6.6 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 172.9, 164.3, 153.3, 141.4, 136.6,136.2, 136.1, 134.6, 134.2, 129.62, 129.55, 127.6, 127.5, 121.3, 119.8,115.3, 79.7, 79.4, 47.0, 35.1, 33.3, 32.6, 32.0, 27.2, 24.5, 23.5, 19.5,19.3, 14.7, 14.2, 8.7; IR: 2963, 2932, 1717, 1636, 1427, 1261, 1111; HRMS(ESI-TOF): Calcd for C 37 H 49 NO3SSi + [M+H] + : 616.3275, found 616.3276; OpticalRotation: [α] D 29.0= -18.0 (c 1.0, CH2Cl2).

[0097] Synthesis of Compound 12

[0098]

[0099] The Grignard reagent was prepared according to the modified Woerpel method: magnesium powder (340 mg, 14.2 mmol, 8.0 eq.) was placed in a flame-dried round-bottom flask equipped with a magnetic stirrer and purged with dry THF (7.0 mL) under argon. A small piece of iodine and a few drops of a propylene chloride mixture were added. After stirring at room temperature for 5–10 minutes until the iodine color disappeared, the reaction mixture was cooled to 0 °C and diluted with dry THF (7.0 mL). A solution of 926 mg, 8.85 mmol, 5.0 eq. of propylene chloride was gradually added to dry tetrahydrofuran (8.9 mL) over 10 minutes, and stirring was continued at this temperature for 0.5 h. The reaction mixture was then heated to room temperature and stirred for 45 minutes. The resulting solution was dropwise through a sleeve into another flame-dried round-bottom flask containing 11 (1.09 g, 1.77 mmol) of dry tetrahydrofuran (8.5 mL). The mixture was maintained at -78 °C under argon until 11 was completely consumed (approximately 30 minutes). The reaction was quenched with saturated ammonium chloride solution (20 mL), and extracted with diethyl ether (20 mL × 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1–20 / 1) to give a colorless oily compound 12 (1.04 g, 86%).

[0100] Data of 12

[0101] TLC: Rf = 0.45 (Petroleum ether / Ethyl acetate = 8 / 1); 1H NMR (600MHz, CDCl3) δ 7.71 – 7.66 (m, 2H), 7.65 – 7.60 (m, 2H), 7.39 (dd, J = 5.1,3.7 Hz, 1H), 7.38 – 7.32 (m, 3H), 7.28 (dd, J = 11.2, 4.2 Hz, 2H), 6.76 (s,1H), 6.21 (s, 1H), 6.00 – 5.84 (m, 1H), 5.33 – 5.15 (m, 2H), 4.95 (t, J = 7.0Hz, 1H), 4.15 (t, J = 6.5 Hz, 1H), 3.41 (d, J = 1.2 Hz, 1H), 3.30 – 3.24 (m,1H), 3.23 – 3.15 (m, 1H), 2.69 (s, 3H), 2.36 – 2.26 (m, 1H), 2.26 – 2.18 (m,1H), 1.96 (dd, J = 6.3, 1.1 Hz, 3H), 1.90 – 1.78 (m, 2H), 1.69 – 1.62 (m,1H), 1.55 (d, J = 0.9 Hz, 3H), 1.49 – 1.43 (m, 1H), 1.37 – 1.28 (m, 1H), 1.25(s, 3H), 1.23 (d, J = 4.1 Hz, 3H), 1.20 – 1.14 (m, 1H), 1.06 (s, 9H), 1.01(d, J = 7.0 Hz, 3H), 0.99 – 0.92 (m, 1H), 0.75 (t, J = 5.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 219.5, 164.2, 153.3, 141.52, 141.47, 137.2, 136.2, 136.1,134.6, 134.2, 129.6, 129.5, 127.6, 127.5, 120.9, 119.8, 115.5, 115.1, 79.8,75.3, 51.9, 40.7, 35.8, 35.1, 32.8, 32.3, 27.2, 25.2, 23.5, 23.4, 23.2, 19.6,19.3, 15.5, 14.2, 10.5; IR: 2960, 2937, 1698, 1427, 1261, 748, 702; HRMS(ESI-TOF): Calcd for C 42 H 60 NO3SSi + [M+H] + : 686.4058, found 686.4059; OpticalRotation: [α] D 24.0 = -19.9 (c 0.88, CH2Cl2).

[0102] Synthesis of Compound 13

[0103]

[0104] Pre-cooled solution 12 (250 mg, 0.36 mmol, 1.0 eq) was added at 0 °C, and the reaction was heated to room temperature and stirred overnight. Then, dihydropyran (DHP) (165 μL, 1.8 mmol, 5.0 eq) and PPTS (9.0 mg, 0.036 mmol, 0.1 eq) were added sequentially at 0 °C, and the mixture was stirred at room temperature for 8 h. The reaction was quenched with saturated NaHCO3 solution. The mixture was diluted with DCM (3.0 mL), and the aqueous phase was extracted with DCM (3.0 mL × 2). The bound organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (petroleum ether / ethyl acetate = 40 / 1) gave a white oily product 13 (239 mg, 85%).

[0105] Data of 13:

[0106] TLC: Rf = 0.7 (Petroleum ether / Ethyl acetate = 8 / 1); 1H NMR (600 MHz,CDCl3) δ 7.68 (d, J = 6.9 Hz, 2H), 7.62 (d, J = 7.1 Hz, 2H), 7.40 (t, J = 7.1Hz, 1H), 7.35 (t, J = 7.3 Hz, 3H), 7.28 (t, J = 7.4 Hz, 2H), 6.75 (s, 1H),6.22 (s, 1H), 6.00 – 5.86 (m, 1H), 5.22 – 5.10 (m, 2H), 5.03 – 4.91 (m, 1H),4.82 (s, 0.4H), 4.54 – 4.46 (m, 1H), 4.15 (t, J = 6.3 Hz, 1H), 4.03 (t, J =9.2 Hz, 0.4H), 3.91 (d, J = 12.1 Hz, 1H), 3.78 (d, J = 8.0 Hz, 0.5H), 3.65(d, J = 2.4 Hz, 0.5H), 3.59 – 3.54 (m, 0.4H), 3.46 – 3.38 (m, 1H), 3.24 –3.14 (m, 1H), 2.69 (s, 3H), 2.34 – 2.27 (m, 1H), 2.27 – 2.18 (m, 1H), 1.96(s, 3H), 1.88 – 1.69 (m, 5H), 1.61 – 1.46 (m, 9H), 1.41 – 1.26 (m, 4H), 1.23(s, 3H), 1.20 (d, J = 6.0 Hz, 3H), 1.15 (d, J = 6.7 Hz, 1.4H), 1.06 (s, 9H),1.04 (d, J = 7.0 Hz, 1.7H), 0.92 (d, J = 6.6 Hz, 1.6H), 0.88 (d, J = 6.7 Hz,1.5H); 13C NMR (150 MHz, CDCl3) δ 216.2, 215.9, 164.22, 164.20, 153.3, 142.7,142.4, 141.43, 141.40, 137.2, 137.0, 136.2, 136.1, 134.5, 134.21, 134.18,129.6, 129.5, 127.6, 127.5, 121.0, 120.8, 119.8, 115.17, 115.15, 114.6,114.3, 101.4, 101.2, 98.7, 83.8, 83.5, 79.7, 79.6, 64.3, 63.9, 63.5, 51.7,51.6, 44.0, 43.8, 37.8, 37.1, 35.15, 35.10, 32.63, 32.60, 31.7, 31.4, 31.1,31.0, 27.2, 26.3, 26.2, 25.6, 25.5, 24.2, 24.1, 23.92, 23.87, 23.6, 21.1,20.8, 20.0, 19.6, 19.4, 18.1, 16.9, 16.5, 15.2, 14.2, 14.2; IR: 2959, 2940,1697, 1636, 1427, 748, 702; HRMS (ESI-TOF): Calcd for C 47 H 68 NO4SSi + [M+H] + :770.4633, found 770.4626; Optical Rotation: [α] D 23.0 = -16.6 (c 1.85, CH2Cl2).

[0107] Synthesis of Compound 14

[0108]

[0109] The catalyst precursor Rh(acac)(CO)2 (2.58 mg, 1.0 × 10⁻⁶) was used. -2 mmol), O-SDPhite (36.4mg, 4×10 -21.0 mmol) and anhydrous toluene (3.0 mL) were added to an 8.0 mL vial. The mixture was stirred at room temperature for 10 minutes to obtain a pale yellow solution. In a glove box, compound 13 (200 mg, 0.26 mmol, 1.0 eq.) was added to a glass vial with a magnetic stir bar, followed by the Rh / O-SDPhite solution prepared above (0.78 mL, 0.0026 mmol, 0.01 eq.), and diluted with 0.52 mL of toluene. The vial was then transferred to a 50 mL autoclave, sealed, and purged three times with syngas CO / H2 (1 / 1) and pressurized to 14 bar. The autoclave was then transferred to a preheated oil bath and stirred at 90 °C for 20 hours, followed by cooling to room temperature. The volatiles were removed by vacuum, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30 / 1-10 / 1) to give a colorless oily product 14 (156 mg, 75%).

[0110] Data of 14:

[0111] TLC: Rf = 0.3 (Petroleum ether / Ethyl acetate = 8 / 1); H NMR (600 MHz,CDCl3) δ 9.77 – 9.70 (m, 1H), 7.68 (d, J = 7.7 Hz, 2H), 7.62 (d, J = 7.5 Hz,2H), 7.40 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.3 Hz, 3H), 7.28 (t, J = 7.4 Hz,2H), 6.76 (s, 1H), 6.22 (s, 1H), 4.96 (q, J = 7.5 Hz, 1H), 4.51 (dd, J = 5.3,2.4 Hz, 1H), 4.15 (t, J = 6.5 Hz, 1H), 3.97 – 3.88 (m, 1H), 3.76 (dd, J =7.9, 2.3 Hz, 1H), 3.63 (dd, J = 5.9, 3.3 Hz, 1H), 3.43 (ddd, J = 11.1, 9.1,4.3 Hz, 1H), 3.25 – 3.15 (m, 1H), 2.69 (s, 3H), 2.35 (dd, J = 13.3, 6.5 Hz,2H), 2.29 (dt, J = 12.3, 6.4 Hz, 1H), 2.24 – 2.17 (m, 1H), 1.95 (s, 3H), 1.88– 1.72 (m, 6H), 1.63 (s, 1H), 1.61 – 1.55 (m, 1H), 1.55 (s, 3H), 1.53 – 1.44(m, 4H), 1.41 – 1.31 (m, 3H), 1.18 (s, 3H), 1.16 (d, J = 6.9 Hz, 2H), 1.10(d, J = 8.6 Hz, 4H), 1.06 (d, J = 6.9 Hz, 12H), 0.94 (d, J = 6.8 Hz, 2H),0.91 (d, J = 6.8 Hz, 1H); 3C NMR (150 MHz, CDCl3) δ 218.1, 217.6, 202.1,201.9, 164.2, 153.3, 141.4, 137.1, 136.9, 136.2, 136.1, 134.5, 134.2, 129.6,129.5, 127.55, 127.48, 121.1, 120.9, 119.80, 119.76, 115.2, 101.4, 101.2,83.6, 83.5, 79.62, 79.58, 64.4, 63.8, 47.7, 47.6, 43.5, 43.2, 39.9 39.8,38.0, 37.2, 35.15, 35.11, 32.6, 32.5, 31.7, 31.4, 31.23, 31.17, 31.1, 31.0,27.2, 26.2, 25.6, 25.5, 24.9, 24.82, 24.79, 24.7, 23.6, 21.1, 20.7, 19.5,19.3, 18.2, 17.1, 16.1, 14.9, 14.3, 14.2; R: 2963, 2860, 1636, 1427, 1261,702; RMS (ESI-TOF): Calculated for C 48 H 70 NO5SSi + [M+H] + : 800.4733, found 800.4738;Optical Rotation: [α] D 22.6 = -27.6 (c 1.65, CH2Cl2).

[0112] Synthesis of Compound 15

[0113]

[0114] At 0 °C, NaH₂PO₄ (57 mg, 0.48 mmol, 2.4 eq.) and 2,3-dimethyl-2-butene (1.0 mL) were added to a tert-butanol / water (1.5 mL / 1.5 mL) solution containing compound 14 (156 mg, 0.2 mmol, 1.0 eq.), followed by the addition of NaClO₂ (58 mg, 0.64 mmol, 3.2 eq.). The mixture was stirred at this temperature for 30 min, then heated to room temperature and stirred for another 30 min. The mixture was diluted with ethyl acetate (10 mL) and washed with water and brine. The combined aqueous solution was further extracted with ethyl acetate (5.0 mL × 2). The organic layer was collected and dried over anhydrous sodium sulfate. After removing the volatiles, the resulting residue was dissolved in 1.0 mL THF, and tetrabutylammonium fluoride (4.0 mL, 4.0 mmol, 1.0 M THF solution, 20 eq.) was added to the flask. The reaction was heated to 40°C and stirred for 6 hours. After completion, the flask was cooled to room temperature and diluted with phosphate buffer (pH 5). The resulting mixture was extracted with ethyl acetate (10 mL × 3). The combined extract was dried over anhydrous sodium sulfate and concentrated. The residue was purified by rapid column chromatography (dichloromethane / methanol = 30 / 1–15 / 1) to give an oily compound 15.

[0115] Data of 15:

[0116] TLC: Rf = 0.3 (Dichloromethane / Methanol = 14 / 1). 1H NMR (600 MHz,CDCl3) δ 6.94 (s, 1H), 6.61 (d, J = 6.4 Hz, 1H), 5.13 (t, J = 6.6 Hz, 1H),4.56 (d, J = 5.4 Hz, 1H), 4.12 (dd, J = 13.5, 6.5 Hz, 1H), 3.93 (dd, J =19.9, 9.3 Hz, 1H), 3.82 – 3.81 (m, 0.5H), 3.71 – 3.64 (m, 0.5H), 3.53 – 3.39(m, 1H), 3.25 (dt, J = 11.3, 7.5 Hz, 1H), 2.71 (s, 3H), 2.40 – 2.18 (m, 4H),2.09 (dt, J = 10.9, 7.8 Hz, 1H), 1.98 (s, 3H), 1.98 – 1.95 (m, 1H), 1.89 –1.72 (m, 4H), 1.69 (s, 3H), 1.63 – 1.54 (m, 1H), 1.46 – 1.32 (m, 2H), 1.20 –1.17 (m, 4.5H), 1.13 (s, 3H), 1.08 (d, J = 6.8 Hz, 1.5H), 0.97 (dd, J = 17.7,6.7 Hz, 3H); 13 C NMR (150 MHz, CDCl3) δ 218.4, 218.2, 176.7, 176.6, 165.4,152.5, 142.3, 142.3, 139.6, 139.3, 120.4, 120.3, 118.8, 118.7, 115.3, 115.2,101.5, 101.1, 84.0, 83.6, 64.3, 63.8, 47.9, 47.7, 43.3, 43.0, 37.9, 36.8,34.3, 34.2, 33.89, 33.86, 32.6, 32.5, 31.7, 31.4, 31.1, 31.0, 29.8, 29.7,26.2, 26.1, 25.6, 25.5, 24.40, 24.36, 24.3, 24.2, 23.7, 21.0, 20.7, 18.9,18.8, 18.2, 16.84, 16.78, 15.6, 14.89, 14.86; HRMS (ESI-TOF): Calcd forC32 H 52 NO6S + [M+H] + : 578.3510, found 578.3514; Optical Rotation: [α] D 20.5 = -6.86 (c 1.05, CH2Cl2).

[0117] Synthesis of 3-deoxy-Epo D

[0118] Compound 15 was dissolved in 20 mL of 0˚C THF solution (0.2 mmol, 1.0 eq.), and 0.31 mL of DIPEA (1.8 mmol, 9.0 eq.) and 95 μL of 2,4,6-trichlorobenzoyl chloride (TCBCl) (0.6 mmol, 3.0 eq.) were added sequentially. The mixture was stirred at 0°C for 1 h and diluted with 30 mL of toluene. This mixture was then added via a syringe pump to 120 mL of 500 mg DMAP (4.0 mmol, 20 eq.) in toluene and incubated at room temperature for 5 h. After addition, stirring was continued for 6 h, and the mixture was concentrated to obtain a white residue. The residue was dissolved in diethyl ether and washed sequentially with 20% ice-cold AcOH, NaHCO3, and NH4Cl. The organic layer was dried on MgSO4, filtered, and concentrated. The crude product was dissolved in MeOH (1.0 mL), and then TsOH (13.8 mg, 0.08 mmol, 0.4 eq.) was added. The mixture was stirred at room temperature for 2 h, then cooled with NaHCO3, extracted with ethyl acetate (5.0 mL × 3), and washed with brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified by rapid column chromatography (petroleum ether / ethyl acetate = 20 / 1–5 / 1) to give a white solid 3-deoxy-epo D (49 mg, 52%).

[0119] Data of 3-deoxy-Epo D:

[0120] TLC: Rf = 0.45 (Petroleum ether / Ethyl acetate = 4 / 1); 11H NMR (600 MHz, CDCl3) δ 6.95 (s, 1H), 6.52 (s, 1H), 5.26 (d, J = 9.3 Hz, 1H), 5.14 (dd, J = 9.1, 4.6 Hz, 1H), 3.69 (s, 1H), 3.20 (dd, J = 6.5, 2.6 Hz, 1H), 2.74 (brs, 1H), 2.71 (s, 3H), 2.69 – 2.61 (m, 1H), 2.37 – 2.25 (m, 2H), 2.19 (d, J = 13.6 Hz, 1H), 2.10 (s, 3H), 2.08 – 2.00 (m, 2H), 1.89 – 1.85 (m, 1H), 1.79 – 1.72 (m, 1H), 1.71 – 1.63 (m, 2H), 1.66 (s, 3H), 1.33 – 1.30 (m, 1H), 1.27 (s, 3H), 1.24 – 1.19 (m, 2H), 1.17 (d, J = 6.7 Hz, 3H), 1.03 (s, 3H), 1.01 (d, J = 7.0 Hz, 3H); 13 13C NMR (150 MHz, CDCl3) δ 220.8, 171.7, 164.9, 152.7, 138.6, 138.3, 121.0, 119.7, 116.4, 79.1, 74.7, 48.2, 40.4, 38.6, 35.5, 32.5, 31.9, 31.6, 26.0, 23.1, 22.1, 19.4, 16.1, 15.3, 14.2; IR: 2963, 2932, 1728, 1636, 1261, 1015, 795; HRMS (ESI-TOF): Calcd for C 27 H 42 NO4S + [M+H] + : 476.2829, found 476.2832; Optical Rotation: [α] D 22.6 = -12.33 (c 0.43, CH2Cl2).

[0121] Synthesis of 3-deoxy-Epo B

[0122]

[0123] At room temperature, 0.45 mL of a solution of H₂O₂ / H₂O / Pyridine = 16 / 140 / 1 and MTO (3.2 mg, 0.013 mmol, 0.5 eq.) were added to 1.2 mL of a DCM solution of 3-deoxy-epo D. The reaction mixture was stirred at room temperature for 1 h, then quenched with saturated NH₄Cl solution and extracted twice with 5.0 mL of DCM. The bound organic layer was dried (Na₂SO₄) and concentrated under vacuum. Purification by preparative high-performance liquid chromatography yielded a colorless oily liquid 3-deoxy-epo B (7.8 mg, 64%).

[0124] Data of 3-deoxy-Epo B:

[0125] TLC: Rf = 0.5 (Petroleum ether / Ethyl acetate = 2 / 1); 1 H NMR (600 MHz, MeOD) δ 7.26 (s, 1H), 6.59 (s, 1H), 5.38 (dd, J = 7.4, 2.6 Hz, 1H), 3.65 (d,J = 9.5 Hz, 1H), 3.27 (dd, J = 9.4, 6.8 Hz, 1H), 2.92 (dd, J = 8.8, 4.3 Hz,1H), 2.69 (s, 3H), 2.46 – 2.40 (m, 1H), 2.21 – 2.12 (m, 2H), 2.08 (s, 3H),1.95 – 1.88 (m, 2H), 1.87 – 1.80 (m, 1H), 1.76 – 1.68 (m, 1H), 1.59 – 1.49(m, 2H), 1.44 – 1.37 (m, 1H), 1.33 (s, 3H), 1.29 (s, 3H), 1.24 – 1.20 (m,1H), 1.20 – 1.10 (m, 2H), 1.18 (d, J = 6.7 Hz, 3H), 1.03 (s, 3H), 1.02 (d, J= 6.2 Hz, 3H); 13C NMR (150 MHz, MeOD) δ 220.1, 173.8, 167.1, 153.1, 139.3,120.9, 118.0, 78.5, 78.2, 63.6, 62.6, 45.2, 37.7, 35.8, 33.7, 33.2, 31.7,30.8, 25.3, 24.8, 23.2, 22.9, 18.7, 17.2, 15.3; IR: 2970, 2940, 1732, 1682,1636, 1454, 1261, 976, 737; HRMS (ESI-TOF): Calcd for C 27 H 42 NO5S + [M+H] + :492.2778, found 492.2783; Optical Rotation: [α] D 21.7 = -6.0 (c 0.15, CH2Cl2).

[0126] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. Those skilled in the art to which this application pertains can make several simple deductions or substitutions without departing from the concept of this application.

Claims

1. A method for synthesizing a key intermediate of epokilin, characterized in that: Compound 1 and trimethylsilyl cyanide undergo an addition reaction in an ether solvent with the aid of lithium chloride to generate compound 2; Compound 2 undergoes a substitution reaction with compound 3 under the action of a base to generate compound 4; compound 4 undergoes an asymmetric hydrogenation reaction under the catalysis of Ir-f-phamidol catalyst to generate compound 5; compound 5 undergoes a condensation reaction with TBDPSCl to generate compound 6; under the catalysis of SeO2, compound 6 reacts with peroxytert-butanol to generate compound 7; under the catalysis of Ru[(S)-DTBM-segephos]OAc2, compound 7 undergoes a hydrogenation reaction to generate compound 8; Compound 8 undergoes an oxidation reaction to form compound 9; Compound 9 undergoes deprotection and reprotection to generate compound 10; wherein, compound 9 is a key intermediate in the synthesis of 3-deoxyepomycin B or 3-deoxyepomycin D, and compound 10 is a key intermediate in the synthesis of epomycin B or epomycin D; Compound 1 is shown as shown in Formula 1, compound 3 is shown as shown in Formula 2, compound 9 is shown as shown in Formula 3, and compound 10 is shown as shown in Formula 4. Formula 1, Formula 2, Formula 3, Formula 4 .

2. The synthesis method according to claim 1, characterized in that: The synthesis method specifically includes the following steps: 。 3. The synthesis method according to claim 1 or 2, characterized in that: The solvent for generating compound 2 is tetrahydrofuran; Optionally, the reaction temperature for generating compound 2 is -30℃ to 80℃.

4. The synthesis method according to claim 1 or 2, characterized in that: The base condition for the formation of compound 4 is a strong base; Optionally, the strong base is lithium bis(trimethylsilylamino)amine, lithium diisopropylamino, sodium hexamethylamino, or potassium hexamethyldisilamino. Optionally, the solvent for generating compound 4 is at least one of tetrahydrofuran, methyl tert-butyl ether, and dioxane; Optionally, the reaction temperature for generating compound 4 is -78°C to room temperature.

5. The synthesis method according to claim 1 or 2, characterized in that: The amount of the Ir-f-phamidol catalyst used is 0.001% to 1% of 4 moles of the compound; Optionally, the reaction solvent for generating compound 5 is tetrahydrofuran, dichloromethane, trichloromethane, or toluene; Optionally, the reaction temperature for generating compound 5 is room temperature.

6. The synthesis method according to claim 1 or 2, characterized in that: The reaction solvent for generating compound 6 is tetrahydrofuran, dichloromethane, or trichloromethane; Optionally, the reaction temperature for generating compound 6 is room temperature; Optionally, the reaction solvent for generating compound 7 is dichloromethane, n-hexane, chloroform, or N,N-dimethylformamide; Optionally, the reaction temperature for generating compound 7 is room temperature.

7. The synthesis method according to claim 1 or 2, characterized in that: The reaction solvent for generating compound 8 is dichloromethane, n-hexane, chloroform, or N,N-dimethylformamide; Optionally, the reaction temperature for generating compound 8 is room temperature; Optionally, the oxidant used in the oxidation reaction of compound 8 to generate compound 9 is a pyridine sulfur trioxide complex; Optionally, the reaction solvent for generating compound 9 is dichloromethane or trichloromethane; Optionally, the reaction temperature for generating compound 9 is room temperature.

8. The synthesis method according to claim 1 or 2, characterized in that: The protecting group removal agent used to generate compound 10 is tetrabutylammonium fluoride; Optionally, the reaction solvent for generating compound 10 is dichloromethane or trichloromethane; Optionally, the reaction temperature for generating compound 10 is room temperature to 50°C.

9. The synthesis method according to claim 1 or 2, characterized in that: The synthesis of epokine B or epokine D from compound 10 includes the following steps: 。 10. The synthesis method according to claim 1 or 2, characterized in that: The synthesis of compound 9 into 3-deoxyepomycin B or 3-deoxyepomycin D includes the following steps: 。

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